NMR Based Metabolomics: An Exquisite and Facile Method for Evaluating Therapeutic Efficacy and Screening Drug Toxicity.

Curr Top Med Chem. 2018;18(20):1827-1849

Authors: Guleria A, Kumar A, Kumar U, Raj R, Kumar D

Abstract
Metabolomics is an analytical approach to metabolism and involves quantitative and comparative analysis of low-molecular-weight metabolites in body fluids or cellular/tissues extracts. Owing to its ability to reveal disease-specific metabolic patterns or metabolic changes produced in response to a therapeutic intervention; it is gaining widespread applications virtually in all aspects of biomedical and pharmaceutical research pertaining to human healthcare management. It has also started playing a strategic role in pharmacological and toxicological research for evaluating therapeutic efficacy/safety of promising drug candidates either alone or in conjunction with other omics tools such as genomics, transcriptomics and proteomics. The metabolic profiling capabilities of nuclear magnetic resonance (NMR) spectroscopy along with pattern recognition methods have successfully been applied for identifying a diagnostic panel of biomarkers, evaluating drug efficacy/safety, screening toxicity and disease mechanism. Particularly, the interest in applying NMR-based metabolomics for the assessment of therapeutic efficacy and safety is increasing among drug researchers and drug regulators owing to its nondestructive, non-selective and minimal sample preparation requirement. On top of this, it offers the potential for high-throughput (i.e. >100 samples a day is attainable) and provides highly reproducible results. In this review, we will discuss some of the recent developments related to NMR based metabolomics followed by some recent literature examples to highlight its potential in (a) the evaluation of therapeutic efficacy and safety of lead discovery compounds, (b) monitoring disease status and recovery after treatment and (c) identification and evaluation of biomarkers of systemic/organ-specific toxicity. Additionally, the review will also highlight its role to facilitate clinical trial testing and improve post-approval drug monitoring.

PMID: 30465509 [PubMed - indexed for MEDLINE]

The current understanding of mesenchymal stem cells as potential attenuators of chemotherapy-induced toxicity.

Int J Cancer. 2018 12 01;143(11):2628-2639

Authors: Rühle A, Huber PE, Saffrich R, Lopez Perez R, Nicolay NH

Abstract
Chemotherapeutic agents are part of the standard treatment algorithms for many malignancies; however, their application and dosage are limited by their toxic effects to normal tissues. Chemotherapy-induced toxicities can be long-lasting and may be incompletely reversible; therefore, causative therapies for chemotherapy-dependent side effects are needed, especially considering the increasing survival rates of treated cancer patients. Mesenchymal stem cells (MSCs) have been shown to exhibit regenerative abilities for various forms of tissue damage. Preclinical data suggest that MSCs may also help to alleviate tissue lesions caused by chemotherapeutic agents, mainly by establishing a protective microenvironment for functional cells. Due to the systemic administration of most anticancer agents, the effects of these drugs on the MSCs themselves are of crucial importance to use stem cell-based approaches for the treatment of chemotherapy-induced tissue toxicities. Here, we present a concise review of the published data regarding the influence of various classes of chemotherapeutic agents on the survival, stem cell characteristics and physiological functions of MSCs. Molecular mechanisms underlying the effects are outlined, and resulting challenges of MSC-based treatments for chemotherapy-induced tissue injuries are discussed.

PMID: 29931767 [PubMed - indexed for MEDLINE]

Dihydropyrimidine dehydrogenase deficiency as a cause of fatal 5-Fluorouracil toxicity.

Autops Case Rep. 2018 Oct-Dec;8(4):e2018049

Authors: Fidai SS, Sharma AE, Johnson DN, Segal JP, Lastra RR

Abstract
5-Fluorouracil (5-FU), in combination with other cytotoxic drugs, is commonly used to treat a variety of cancers. Dihydropyrimidine dehydrogenase (DPD) catalyzes the first catabolic step of the 5-FU degradation pathway, converting 80% of 5-FU to its inactive metabolite. Approximately 0.3% of the population demonstrate complete DPD deficiency, translating to extreme toxicity of 5-FU. Here we present a case of a patient who had a fatal outcome after treatment with 5-FU who was found to have an unknown DPD deficiency discovered at autopsy.

PMID: 30775324 [PubMed]

Drug-Drug Interactions of Infectious Disease Treatments in Low Income Countries: A Neglected Topic?

Clin Pharmacol Ther. 2019 Feb 16;:

Authors: McFeely SJ, Yu J, Zhao P, Hershenson S, Kern S, Ragueneau-Majlessi I, Hartman D

Abstract
Despite recent advances in recognizing and reducing the risk of drug-drug interactions (DDIs) in developed countries, there are still significant challenges in managing DDIs in low income countries (LICs) worldwide. In the treatment of major infectious diseases in these regions, multiple factors contribute to ineffective management of DDIs that lead to loss of efficacy or increased risk of adverse events to patients. Some of these difficulties, however, can be overcome. This review aims to evaluate the inherent complexities of DDI management in LICs from pharmacological standpoints and illustrates the unique barriers to effective management of DDIs, such as the challenges of co-infection and treatment settings. A better understanding of comprehensive drug-related properties, population-specific attributes, such as physiological changes associated with infectious diseases, and the use of modeling and simulation techniques are discussed, as they can facilitate the implementation of optimal treatments for infectious diseases at the individual patient level. This article is protected by copyright. All rights reserved.

PMID: 30771252 [PubMed - as supplied by publisher]

Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study.

Neuromuscul Disord. 2018 Dec 17;:

Authors: Pena LDM, Barohn RJ, Byrne BJ, Desnuelle C, Goker-Alpan O, Ladha S, Laforêt P, Mengel KE, Pestronk A, Pouget J, Schoser B, Straub V, Trivedi J, Van Damme P, Vissing J, Young P, Kacena K, Shafi R, Thurberg BL, Culm-Merdek K, van der Ploeg AT, NEO1 Investigator Group

Abstract
This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t1/2z∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.

PMID: 30770310 [PubMed - as supplied by publisher]

Procalcitonin, mid-regional proadrenomedullin and C-reactive protein in predicting treatment outcome in community-acquired febrile urinary tract infection.

BMC Infect Dis. 2019 Feb 14;19(1):161

Authors: Stalenhoef JE, van Nieuwkoop C, Wilson DC, van der Starre WE, van der Reijden TJK, Delfos NM, Leyten EMS, Koster T, Ablij HC, van 't Wout JJW, van Dissel JT

Abstract
BACKGROUND: A reduction in duration of antibiotic therapy is crucial in minimizing the development of antimicrobial resistance, drug-related side effects and health care costs. The minimal effective duration of antimicrobial therapy for febrile urinary tract infections (fUTI) remains a topic of uncertainty, especially in male patients, those of older age or with comorbidities. Biomarkers have the potential to objectively identify the optimal moment for cessation of therapy.
METHODS: A secondary analysis of a randomized placebo-controlled trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days. Patients indicated to receive antimicrobial treatment for more than 14 days were excluded from randomization. The biomarkers procalcitonin (PCT), mid-regional proadrenomedullin (MR-proADM), and C-reactive protein (CRP) were compared in their ability to predict clinical cure or failure through the 10-18 day post-treatment visit.
RESULTS: Biomarker concentrations were measured in 249 patients, with a clinical cure rate of 94% in the 165 randomized and 88% in the 84 non-randomized patients. PCT, MR-proADM and CRP concentrations did not differ between patients with clinical cure and treatment failure, and did not predict treatment outcome, irrespective of 7 or 14 day treatment duration (ROCAUC 0.521; 0.515; 0.512, respectively). PCT concentrations at presentation were positively correlated with bacteraemia (τ = 0.33, p < 0.001) and presence of shaking chills (τ = 0.25, p < 0.001), and MR-proADM levels with length of hospital stay (τ = 0.40, p < 0.001), bacteraemia (τ = 0.33, p < 0.001), initial intravenous treatment (τ = 0.22, p < 0.001) and time to defervescence (τ = 0.21, p < 0.001). CRP did not display any correlation to relevant clinical parameters.
CONCLUSIONS: Although the biomarkers PCT and MR-proADM were correlated to clinical parameters indicating disease severity, they did not predict treatment outcome in patients with community acquired febrile urinary tract infection who were treated for either 7 or 14 days. CRP had no added value in the management of patients with fUTI.
TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].

PMID: 30764769 [PubMed - in process]

Evaluation of pharmaceutical toxic effects of non-standard endpoints on the macrophyte species Lemna minor and Lemna gibba.

Sci Total Environ. 2019 Mar 20;657:926-937

Authors: Alkimin GD, Daniel D, Frankenbach S, Serôdio J, Soares AMVM, Barata C, Nunes B

Abstract
In the last years the environmental presence of pharmaceuticals has gained increasing attention. Research data show that these compounds can cause toxicological effects in different species of fish, mollusks and macroinvertebrates. However, the literature is scarce in terms of ecotoxicity data especially focusing on plants as test organisms. Ecotoxicological plant-based tests following the standard OEDC guideline 221 (OECD, 2006) are strongly restricted due to the recommended end-points: growth and yield of plants. It is necessary to develop and validate alternative macrophyte-based tests (non-standard endpoints), more sensible and providing additional information about the chemical contamination effects in plants. To attain this purpose, species from the Lemna genus were selected. Thus, the aim of this study was to analyze the toxic effects of pharmaceuticals in non-standard endpoints on two macrophyte species, Lemna minor and Lemna gibba. To this purpose an acute assay (96 h) was performed with L. minor and L. gibba exposed to chlorpromazine (CPZ), paracetamol (APAP), and diclofenac (DCF), in the following concentration ranges: 0 to 20 μg/L, 0 to 125 μg/L, and 0 to 100 μg/L, respectively. The analyzed endpoints were: levels of chlorophyll a and b, total chlorophyll, carotenoids, anthocyanins; chlorophyll fluorescence; and catalase activity. In general, higher concentrations of the tested pharmaceuticals caused significant effects on both Lemna species in terms of the different endpoints analyzed. In conclusion, acute exposures to CPZ, APAP, and DCF differently affected the defensive system of the tested species; among chlorophylls, chlorophyll b content was more affected, but pharmaceutical exposure was not able to cause alterations on chlorophyll fluorescence.

PMID: 30677958 [PubMed - indexed for MEDLINE]

The contribution of Ghanaian patients to the reporting of adverse drug reactions: a quantitative and qualitative study.

BMC Public Health. 2018 Dec 18;18(1):1384

Authors: Jacobs TG, Hilda Ampadu H, Hoekman J, Dodoo ANO, Mantel-Teeuwisse AK

Abstract
BACKGROUND: Under-reporting of adverse drug reactions (ADRs) is a major challenge for pharmacovigilance in Africa. This study sets out to assess the level of awareness of Ghanaian patients about ADRs and ADR-reporting and explores how different patients in Ghana recognize an ADR and the steps they take when they experience an ADR.
METHODS: This was a two-part study consisting of a survey to quantify the awareness of Ghanaian patients on ADRs and ADR-reporting, and in-depth interviews to explore how patients recognize an ADR and the steps they take thereafter. Participants were selected from 28 health care facilities (HCF) in rural and urban areas in 4 out of the 10 administrative regions of Ghana. Chi-square tests were used to examine associations between demographic variables and i) awareness of ADRs and ADR-reporting, ii) ADR experience and iii) awareness of the Ghana Food and Drug Authority (Ghana-FDA) and its patient reporting system (PRS). Only participants that indicated they experienced an ADR were included for the in-depth interviews. Data was investigated for participants' awareness of ADRs, ADR reporting and steps taken when they experience ADRs.
RESULTS: Of the total 572 participants enrolled in the study, 14% indicated they were unaware of ADRs and were excluded. Of the remaining 491 participants, 38% had experienced an ADR, of which 67% reported the ADR, 68% of them reported it to a doctor. Only 3% of the 491 participants were aware of the Ghana-FDA's PRS. The interview phase consisted of 33 patients who had experienced an ADR. Three key findings from the interview phase were; most participants recognized an ADR themselves, the symptoms of the ADR were the most mentioned reason for reporting and participants experienced a wide variety of obstacles in ADR-reporting.
CONCLUSIONS: Most Ghanaian patients appear unaware of or unable/unwilling to use formal national channels for ADR reporting like the Ghana-FDA PRS. Motivation for ADR reporting appeared mainly personal and not communal. These findings warrant further attention in order to increase patient reporting of ADRs.

PMID: 30563498 [PubMed - indexed for MEDLINE]

Substitution has better efficacy than add-on therapy for patients with focal epilepsy after their first antiepileptic drug treatments fail.

Seizure. 2019 Jan;64:23-28

Authors: Wang X, He R, Zeng Q, Wang Y, Zhu P, Bao Y, Du Y, Shen J, Zheng R, Xu H

Abstract
PURPOSE: This study is to compare the efficacy of substitution with add-on therapy in patients with focal epilepsy, whose first monotherapy has failed after receiving usual treatments.
METHODS: This is a prospective, long-term, non-randomized observational cohort study. Data were collected from Wenzhou Epilepsy Follow Up Registry Database. Focal epilepsy patients from January 2003 to June 2015, whose first monotherapy had failed, were registered. The total observation period was three years. The major outcome measure was seizure remission rate. The secondary outcome measures included retention rates and incidences of intolerable adverse events.
RESULTS: A total of 596 patients were included, among them 209 received substitution therapy, and 387 received add-on therapy. Seizure remission rates were 56.5% by substitution therapy and 39.0% by add-on therapy, respectively (p = 0.025). Retention rate was 49.3% by substitution therapy, and 36.2% by add-on therapy (p = 0.031). Incidence of intolerable adverse events for substitution and add-on was 4.8% and 7.2%, respectively (p = 0.243). There were 457 patients who failed to the first monotherapy due to lack of efficacy. In these patients, seizure remission rates of substitution and add-on were 51.0% and 38.1%, respectively (p = 0.171). Retention rates were 48.1% and 36.0%, respectively (p = 0.136). And, incidences of intolerable adverse events were 2.9% and 6.8%, respectively (p = 0.137).
CONCLUSION: The seizure remission rate and retention rate of substitution therapy are better than those of add-on therapy for focal epilepsy patients whose first monotherapy fails.

PMID: 30529755 [PubMed - indexed for MEDLINE]

Incidence of infusion hypersensitivity reaction after withholding dexamethasone premedication in early breast cancer patients not experiencing two previous cycles of infusion hypersensitivity reaction for weekly paclitaxel chemotherapy.

Support Care Cancer. 2018 Jul;26(7):2471-2477

Authors: Parinyanitikul N, Tanpipattanakul W, Poovorawan N, Rattananupong T, Laoitthi P, Sithidetphaiboon P, Thanasanvimon S, Sriuranpong V

Abstract
BACKGROUND: Premedication with dexamethasone is an essential part of the prevention of hypersensitivity reaction (HSR) associated with taxane administration. However, the possibility of stopping dexamethasone premedication has been investigated in previous studies to reduce the steroid's adverse events; however, either the result or the particular protocol was limited. Thus, our study aimed to evaluate the incidence of HSR after dexamethasone premedication discontinuation after lack of HSR in two previous weekly paclitaxel infusions.
METHOD: Early breast cancer patients who received adjuvant weekly paclitaxel in a retrospective cohort from January 2012 through February 2016 at the King Chulalongkorn Memorial Hospital were reviewed. All patients received a standard premedication protocol prior to the first and second paclitaxel infusion. Dexamethasone was omitted in later cycles in all patients who did not undergo infusion HSR. Patients who developed HSR during the first or second cycles of paclitaxel infusion were excluded. The incidence of HSR during the later cycle of paclitaxel administration and factors associated with this adverse reaction were collected.
RESULTS: Eighty-one of 85 patients who did not undergo infusion HSR after 2 cycles of weekly paclitaxel administration were retrospectively reviewed. The median age was 51 years (range 27-74 years). Only 16% of the patients had a BMI greater than 30 kg/m2, 57.8% were premenopausal, 67.9% had no comorbidity, none had a history of allergy or asthma, 65.4% received weekly paclitaxel as a single agent, and 34.6% received weekly paclitaxel in combination with trastuzumab. Five of 81 patients reported grade I-II HSR (6.25%), which occurred mostly during the first 6 cycles (60%). Temporary discontinuation of paclitaxel infusion was observed in all HSR patients. No differences regarding age, BMI, menopausal status, and underlying disease between the HSR and no HSR groups were identified. Concerning the safety profile, peripheral neuropathy (gr I 60%, gr II 13.5%, and gr III 2.4%), myalgia (43.4%), and edema (10.5%) were commonly reported, whereas dyspepsia (5.3%) and insomnia (14.5%) were rarely described in withholding patients.
CONCLUSION: Withholding dexamethasone premedication in non-experiencing HSR patients after two previous cycles of weekly paclitaxel administration was safe and did not impact the higher incidence of HSR. A discontinuing dexamethasone protocol should be recommended generally in these patients, especially those with a high risk for steroid-induced side effects.

PMID: 29435713 [PubMed - indexed for MEDLINE]

Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies.

Mayo Clin Proc. 2018 04;93(4):509-517

Authors: Jansson-Knodell CL, Hujoel IA, Rubio-Tapia A, Murray JA

Abstract
Enteropathies can be overwhelming for clinicians. There is a wide spectrum of diseases involved; their effect on patients can be severe; and their underlying cause can be obscure. In this article, we outline a practical approach to enteropathies that are most common and not to be missed and is applicable to general and specialist physicians.

PMID: 29622097 [PubMed - indexed for MEDLINE]

Pediatric Poisonings: Do They Really Need That PICU Bed?

Pediatr Crit Care Med. 2017 07;18(7):727-728

Authors: Bateman ST

PMID: 28691966 [PubMed - indexed for MEDLINE]

Phase I Study of BI 853520, an Inhibitor of Focal Adhesion Kinase, in Patients with Advanced or Metastatic Nonhematologic Malignancies.

Target Oncol. 2019 Feb 11;:

Authors: de Jonge MJA, Steeghs N, Lolkema MP, Hotte SJ, Hirte HW, van der Biessen DAJ, Abdul Razak AR, De Vos FYFL, Verheijen RB, Schnell D, Pronk LC, Jansen M, Siu LL

Abstract
BACKGROUND: Overexpression/activation of focal adhesion kinase (FAK) in human malignancies has led to its evaluation as a therapeutic target. We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor.
OBJECTIVE: Our objectives were to identify the maximum tolerated dose (MTD), and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker expression, and preliminary activity.
PATIENTS AND METHODS: The study comprised a standard 3 + 3 dose-escalation phase followed by an expansion phase in patients with selected advanced, nonhematologic malignancies.
RESULTS: Thirty-three patients received BI 853520 in the dose-escalation phase; the MTD was 200 mg once daily (QD). Dose-limiting toxicities included proteinuria and fatigue, both of which were grade 3. Preliminary PK data supported QD dosing. In the expansion cohort, 63 patients received BI 853520 200 mg QD. Drug-related adverse events (AEs) in > 10% of patients included proteinuria (57%), nausea (57%), fatigue (51%), diarrhea (48%), vomiting (40%), decreased appetite (19%), and peripheral edema (16%). Most AEs were grade 1-2; grade 3 proteinuria, reported in 13 patients (21%), was generally reversible upon treatment interruption. Nineteen patients underwent dose reduction due to AEs, and three drug-related serious AEs were reported, none of which were fatal. Preliminary PD analysis indicated target engagement. Of 63 patients, 49 were evaluable; 17 (27%) achieved a best response of stable disease (4 with 150 + days), and 32 (51%) patients had progressive disease.
CONCLUSIONS: BI 853520 has a manageable and acceptable safety profile, favorable PK, and modest antitumor activity at an MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies. CLINICALTRIALS.
GOV IDENTIFIER: NCT01335269.

PMID: 30756308 [PubMed - as supplied by publisher]

Effect of Systematic Conversion to Generic Mycophenolate Mofetil (MMF) in Kidney Transplantation: A Single-Center Clinical Experience from Japan.

Transplant Proc. 2018 Dec;50(10):3255-3257

Authors: Hirano H, Matsunaga T, Maenosono R, Taniguchi S, Uehara H, Nomi H, Kano Y, Fujiwara Y, Ichihashi A, Kobayashi D, Tsutsumi T, Komura K, Ibuki N, Inamoto T, Matsumura H, Ashida A, Azuma H

Abstract
INTRODUCTION: Recently, more and more generic drugs have been used for immunosuppressive drugs in the field of organ transplantation. Some reports have indicated that blood concentration of most generic drugs is difficult to maintain stability, and it may cause the difference in graft survival of transplanted organs between original drugs and generic drugs. In this article, we report the cases could not maintain blood concentration of generic drugs of mycophenolate mofetil (MMF).
RESULTS: In 4 cases out of 5 cases that we had to change original MMF to generic MMF, there were cases that blood concentration level was not stabilized. There were possibility that the lowered blood concentration level of MMF caused a rejection, in two cases. Mean MMF trough level was decreased from 3.6 ± 1.9 μg/mL to 0.6 ± 0.4 μg/mL. Due to the early detection, it did not become severe or failure of graft function, however, we cannot deny the possibilities that side effects were increased and rejection rose. In these cases, we discontinued to use the generic drugs thereafter due to unstable plasma concentration of MMF.
DISCUSSION: Some reports have indicated that failure to maintain plasma concentration of MMF leads to rejection. Therefore, maintenance of effective plasma concentration and prevention of rejection are essential to long-term graft survival in kidney transplant.
CONCLUSION: Generic drug formulations may exhibit differences in effects and absorption compared to the brand-name drug. If the generic drug should be used, patients should be closely monitored.

PMID: 30577194 [PubMed - indexed for MEDLINE]

Development of torsadogenic risk assessment using human induced pluripotent stem cell-derived cardiomyocytes: Japan iPS Cardiac Safety Assessment (JiCSA) update.

J Pharmacol Sci. 2018 Dec;138(4):233-239

Authors: Kanda Y, Yamazaki D, Osada T, Yoshinaga T, Sawada K

Abstract
Cardiac safety assessment is challenging because a better understanding of torsadogenic mechanisms beyond hERG blockade and QT interval prolongation is necessary for patient safety. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a new human cell-based platform to assess cardiac safety in non-clinical testing during drug development. The multi-electrode array (MEA) platform is a promising electrophysiological technology to assess QT interval prolongation and proarrhythmic potential of drug candidates using hiPSC-CMs. The Japan iPS Cardiac Safety Assessment (JiCSA) has established an MEA protocol to evaluate the applicability of hiPSC-CMs for assessing the torsadogenic potential of compounds and completed a large-scale validation study using 60 compounds. During our study, an international multi-site study of hiPSC-CMs was performed by the Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative using 28 compounds. We have comparatively analyzed our JiCSA datasets with those of CiPA using the CiPA logistical and ordinal linear regression model. Regardless of the protocol differences, the evaluation results of the 28 compounds were very similar and highly predictable for torsadogenic risks. Thus, an MEA-based approach using hiPSC-CMs would be a standard testing method to evaluate proarrhythmic potentials. This review paper would provide new insights into the hiPSC-CMs/MEA method required for its regulatory use.

PMID: 30415824 [PubMed - indexed for MEDLINE]

Application of the comparison approach to open TG-GATEs: A useful toxicogenomics tool for detecting modes of action in chemical risk assessment.

Food Chem Toxicol. 2018 Nov;121:115-123

Authors: Heusinkveld HJ, Wackers PFK, Schoonen WG, van der Ven L, Pennings JLA, Luijten M

Abstract
Mode of action information is one of the key components for chemical risk assessment as mechanistic insight leads to better understanding of potential adverse health effects of a chemical. This insight greatly facilitates assessment of human relevance and enhances the use of non-animal methods for risk assessment, as it ultimately enables extrapolation from initiating events to adverse effects. Recently, we reported an in vitro toxicogenomics comparison approach to categorize (non-)genotoxic carcinogens according to similarities in their proposed modes of action. The present study aimed to make this comparison approach generally applicable, allowing comparison of outcomes across different studies. The resulting further developed comparison approach was evaluated through application to toxicogenomics data on 18 liver toxicants in human and rat primary hepatocytes from the Open TG-GATEs database. The results showed sensible matches between compounds with (partial) overlap in mode of action, whilst matches for compounds with different modes of action were absent. Comparison of the results across species revealed pronounced and relevant differences between primary rat and human hepatocytes, underpinning that information on mode of action enhances assessment of human relevance. Thus, we demonstrate that the comparison approach now is generally applicable, facilitating its use as tool in mechanism-based risk assessment.

PMID: 30096367 [PubMed - indexed for MEDLINE]

Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 (BMS-936559).

Crit Care Med. 2019 Feb 08;:

Authors: Hotchkiss RS, Colston E, Yende S, Angus DC, Moldawer LL, Crouser ED, Martin GS, Coopersmith CM, Brakenridge S, Mayr FB, Park PK, Ye J, Catlett IM, Girgis IG, Grasela DM

Abstract
OBJECTIVES: To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559, Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression.
DESIGN: Randomized, placebo-controlled, dose-escalation.
SETTING: Seven U.S. hospital ICUs.
STUDY POPULATION: Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/μL.
INTERVENTIONS: Participants received single-dose BMS-936559 (10-900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels.
MEASUREMENTS AND MAIN RESULTS: The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose: 2/4; 30 mg: 2/4; 100 mg: 1/4; 300 mg: 1/4; 900 mg: 0/4; placebo: 0/4). All participants had adverse events (75% grade 1-2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1-2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days.
CONCLUSIONS: In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis.

PMID: 30747773 [PubMed - as supplied by publisher]

Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial.

Lancet Oncol. 2019 Feb 07;:

Authors: de Bono JS, Concin N, Hong DS, Thistlethwaite FC, Machiels JP, Arkenau HT, Plummer R, Jones RH, Nielsen D, Windfeld K, Ghatta S, Slomovitz BM, Spicer JF, Yachnin J, Ang JE, Mau-Sørensen PM, Forster MD, Collins D, Dean E, Rangwala RA, Lassen U

Abstract
BACKGROUND: Tisotumab vedotin is a first-in-human antibody-drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor.
METHODS: InnovaTV 201 is a phase 1-2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing.
FINDINGS: Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2-22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment.
INTERPRETATIONS: Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours.
FUNDING: Genmab A/S.

PMID: 30745090 [PubMed - as supplied by publisher]

Real world study of regimen containing bevacizumab as first-line therapy in Chinese patients with advanced non-small cell lung cancer.

Thorac Cancer. 2018 07;9(7):805-813

Authors: Xing P, Mu Y, Wang Y, Hao X, Zhu Y, Hu X, Wang H, Liu P, Lin L, Wang Z, Li J

Abstract
BACKGROUND: Large scale randomized controlled trials have demonstrated that the use of bevacizumab in addition to chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) conveys significant survival benefits. We explored the clinical impact of a first-line regimen containing bevacizumab (B+) versus a non-bevacizumab regimen (non-B) in advanced non-squamous NSCLC (NS-NSCLC) patients in a real world setting.
METHODS: The medical records of patients with advanced NS-NSCLC who received first-line therapy with or without bevacizumab were retrospectively collected. The primary outcome was progression-free survival (PFS), with secondary objectives of objective response rate (ORR), disease control rate (DCR), and safety. Exploratory analysis of EGFR and ALK status was conducted in subgroup.
RESULTS: One hundred and forty-nine patients met the selection criteria: 62 in the B+ and 87 in the non-B group. The baseline characteristics were well balanced. In the overall population, the median PFS was significantly longer in the B+ than in the non-B group (9.7 vs. 7.0 months, hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.30-0.91; P = 0.0184). Improved trends in both ORR and DCR were observed in the B+ group. In wild-type patients, the median PFS of the B+ was 11.3 compared to 5.5 months in the non-B group (HR 0.43, 95% CI 0.20-0.91; P = 0.0234). In wild type and unknown populations, the median PFS was 11.3 (B+) compared to 6.0 months (non-B) (HR 0.53; 95% CI 0.28-1.02; P = 0.0520). The safety profile was acceptable in both groups and no unexpected findings were observed.
CONCLUSION: Our analysis confirmed that a first-line regimen containing bevacizumab showed superior clinical benefits over a non-bevacizumab regimen in Chinese patients with advanced NS-NSCLC in a real world setting.

PMID: 29768721 [PubMed - indexed for MEDLINE]

Fluoropyrimidine-induced intestinal mucosal injury is associated with the severity of chemotherapy-related diarrhea.

Scand J Gastroenterol. 2019 Feb 10;:1-6

Authors: Ota K, Takeuchi T, Kojima Y, Harada S, Ozaki H, Sugawara N, Hirata Y, Yamaguchi T, Terazawa T, Kakimoto K, Kii T, Goto M, Higuchi K

Abstract
BACKGROUND AND AIM: Although the fluoropyrimidines are effective chemotherapeutic agents for malignant gastrointestinal tumors, they sometimes cause enteritis with diarrhea. Severe treatment-related diarrhea may result in chemotherapy discontinuation. We investigated the relationship between diarrhea severity and fluoropyrimidine-induced small intestinal mucosal injury.
METHODS: We performed small bowel capsule endoscopy in patients undergoing chemotherapy including fluoropyrimidine for a malignant tumor between May 2017 and June 2018 and analyzed the relationship between the endoscopic findings and diarrhea severity. We also performed a cross-sectional analysis of patient factors and routes of chemotherapy to identify risk factors of fluoropyrimidine-induced small intestinal injury.
RESULTS: Small bowel capsule endoscopy was successfully completed in 16 eligible patients. The diarrhea grade (per the Common Terminology Criteria for Adverse Events, version 4.0) was significantly correlated with the percentage of patients with a small intestinal mucosal break (grade 0, 16.7%; grade 1, 57.1%; grade 2, 100%; p = .016, Cochran-Armitage trend test). Compared to patients receiving intravenous therapy, those receiving an orally administered fluoropyrimidine had a significantly greater number of small intestinal mucosal breaks (median number of breaks [range]; intravenous 5-fluorouracil, 0 [0-13]; oral fluoropyrimidine, 6.5 [1-20]; p = .0162, Mann-Whitney U test).
CONCLUSIONS: Many patients with diarrhea caused by chemotherapy including fluoropyrimidine had small intestinal mucosal breaks. Additionally, small intestinal mucosal breaks were more severe in patients receiving a regimen of oral treatment than in those receiving a regimen of intravenous therapy. These outcomes have important implications for investigations of new strategies for preventing anti-cancer drug-induced diarrhea.

PMID: 30739515 [PubMed - as supplied by publisher]